Nucleoside reverse transcriptase inhibitor resistance

Nucleoside reverse transcriptase inhibitors (NRTIs) comprise the first clas s of drug with proven antiretroviral efficacy against HIV-1, and the first in which drug resistance was reported. Ongoing research in the area of NRTI resistance and cross-resistance contributes much to what we know about the failure of antiretroviral therapy. The genetic mutation patterns responsib le for resistance to the available NRTIs have been well documented. This in formation is being used to plan rational drug therapy. Furthermore, it serv es as the standard against which to evaluate response patterns to multiple- drug regimens, ultimately enabling more accurate prediction of outcome with combination therapies. Other features of NRTI resistance, such as the theo retic reversal of zidovudine resistance associated with the M184V mutation or the powerful influence of the Q151M multiple-drug resistance mutation, h ave revealed the unpredictable nature of HIV resistance and how much we sti ll need to learn. Although NRTIs are the cornerstone of antiretroviral ther apy at present and are used to control disease progression for extended per iods, it is clear that eventually resistance occurs with all antiretroviral regimens. Future research into NRTI-resistance mutations, mutational inter actions, treatment sequencing, and viral fitness and fidelity will continue to refine our understanding of drug resistance and improve our ability to delay or eliminate resistance and advance HN control.